In 2006, the American Cancer Society estimates a nationwide 174,470 new cases and 162,460 deaths from lung cancer, one of the most deadly malignancies that kills up to 3 millions annually worldwide. Radiation combined with chemotherapy is the treatment of choice for most patients with advanced disease. However, only a minority of them can receive high-dose radiation due to the risk of radiation-induced lung toxicity. Amifostine as the only FDA-approved radioprotector does not protect the lung and produces substantial toxicity by itself. Therefore, there is an urgent need for developing improved radioprotectors. We have made important findings. First, radiation increases lung TNF-alpha and TGF-beta1 productions that cause lung damage in mice. Reduction of lung TNF receptor 1 (TNFR1) by antisense oligonucleotide (ASO) or by genetic knock-out in mice is radioprotective by decreasing lung apoptosis and improving pulmonary function, in addition to the protection by inhibiting TGF-beta 1 activity. We hypothesize that combined TNF-alpha and TGF-beta1 targeted therapy may provide an improved radioprotection in the lung. The goals of this application are to understand the roles of TNF-alpha and TGF-beta1 and their receptors in radiation-induced lung toxicity and to develop therapeutic blocking agents as radioprotectors. In Specific Aim 1, we will study the roles of both cytokines and their receptors in radiation-induced lung toxicity such as fibrosis and reduced lung function in a mouse model. Knock-out mice for TNFR1 and Smad3 will be used to validate the radioprotection strategy. In Specific Aim 2, we will optimize the use of ASO for specific inhibition of TNFR1 and Smad3 pathways in mouse lung as protectors against a single dose and fractionated radiation. In Specific Aim 3, we will conduct therapeutic experiments to assess the potential benefit of combining TNFR1 and smad3 inhibition for protection against radiation in mice lung cancer xenograft model. Therapeutic effect will be determined by evaluating both normal lung protection and tumor sensitivity to radiation. These studies will provide insights on the mechanisms of radiation-induced lung tissue damage, leading to the development of improved radioprotectors. PUBLIC HEALTH RELEVANCE: Radiation-caused normal lung damage greatly limits the treatment effect of radiotherapy for thoracic cancers including lung cancer. Although the action of cytokine TGF-beta1 during radiation has been known to induce lung toxicity, blocking this action is not completely radioprotective because other mechanisms may also be involved. In this application, we propose to block actions for both TGF-beta1 and TNF-alpha, a pathway that we previously demonstrated be crucial in radiation lung toxicity, by using specific antisense oligonucleotides to achieve improved lung radioprotection.